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THE excellent article by Williams et al.
in this issue of the Journal highlights the issue of drug response during development by examining the developmental regulation of codeine metabolism and analgesia in a rat model. 1 It is well recognized that in humans, codeine is metabolized to its active metabolite morphine; without this metabolism, analgesia is limited. The O-demethylation of codeine to morphine is mediated by the cytochrome (CYP) P-450 enzyme CYP2D6, an enzyme responsible for the metabolism of a wide range of drugs (, accessed September 21, 2003). Genetic polymorphism exists for CYP2D6, and individuals can be classified into two groups: extensive and poor metabolizers. Poor metabolizers (who lack active CYP2D6) do not produce morphine; therefore, codeine does not provide efficacious analgesia. What is the situation for neonates? Can they be classified into poor or extensive metabolizers at birth on the basis of phenotype? The present investigators showed that in rats, codeine metabolism is indeed developmentally regulated, with low efficacy in the early postnatal period. 1

Development has an important effect on CYP P-450 enzymes; apparently quite soon after birth CYP2D6 activity increases markedly in humans. 2 Other CYP enzyme activities also appear during the first weeks of life. It is important to recognize that the current study was performed in a rat model using the Dark Agouti rat, which has impaired metabolism of debrisoquine and absence of CYP2D1, in contrast to the control, Sprague-Dawley rats. 3 However, it is now apparent that CYP2D2 expression is also reduced in Dark Agouti rats and that although CYP2D2 also catalyzes debrisoquine metabolism, there are differences in the substrates metabolized by CYP2D1 and CYP2D2. 3 Thus, the Dark Agouti rat is an imperfect model for the polymorphic reduction in CYP2D6 expression in humans. The relationship between CYP2D1 and CYP2D2 development in rats does not necessarily translate to similar developmental changes in CYP2D6 in humans, and it would be dangerous to make such a leap.

Narcotic analgesics have long been administered to neonates and children, despite a fundamental lack of pharmacologic knowledge. In 1965, Way et al.4 studied the effect of morphine and meperidine on the carbon dioxide respiratory response curve and demonstrated that morphine shifts the curve in the newborn infant downward and to the right to a greater extent than meperidine. 4 From these data, it was suggested that meperidine depresses the infant’s respiration less than morphine, perhaps because of an immature, “leaky” blood-brain barrier, allowing a greater amount of morphine to cross the blood-brain barrier and gain access to receptor sites within the central nervous system. This highlights that drug metabolism is not the only pharmacokinetic variable that may change during development. Currently, we recognize the importance of a drug efflux transporter protein-P glycoprotein present in the gut and endothelial cells in the blood-brain barrier. This transporter limits drug absorption from the gut and its passage into the brain. 5,6 Other uptake and efflux transporters are also expressed in the brain and control brain drug uptake. The brain and gut are not the only sites where protein-P glycoprotein can be identified. Absence or pharmacologic blockade of placental protein-P glycoprotein, for example, increases fetal drug exposure. 7 Studies are required to define the activity of protein-P glycoprotein and other transporters in various tissues of the body as the neonate matures; such investigation may allow the variability of drug response to be addressed on a more rational basis, leading to the individualization of drug therapy in neonates and small children as they mature and develop.

Human studies are urgently required. Although such clinical studies are difficult to perform in patients ranging in age from neonates to adolescents, they are essential to the development of rational drug dosing in children. Such studies will be stimulated by the Best Pharmaceuticals for Children Act, signed into law in 2002 (, accessed September 21, 2003). This and the Pediatric Rule have stimulated such clinical investigation (, accessed September 21, 2003). Thus, to quote Kearns et al.
, “The provision of safe and effective drug therapy for children requires a fundamental understanding and integration of the role of ontogeny in the disposition and action of drugs.”8

Does this mean all drugs must be studied in children of all ages? Fortunately, the answer is probably “No.” We currently have an understanding of the factors influencing drug absorption, distribution, metabolism, and transport as well as renal excretion. For most of these processes, model compounds are available and could be used to evaluate their activity in children. Evaluation of such model compounds will allow cautious extrapolation to other substrates, which are handled in a similar fashion. Such extrapolation can be made more confidently when large differences are found.

The classic example of the blue baby syndrome induced by chloramphenicol administration is a much-cited example of a drug-induced adverse effect in neonates resulting from their impaired drug metabolism. Fortunately, other examples of such serious consequences of impaired drug metabolism have been rare. The issue of pain control in children is correctly recognized to be of great clinical importance. 9 Defining the underlying factors responsible for variability in pain control in children of all ages will require definition of the variability of plasma drug concentrations (e.g.
, morphine in this study), the mechanisms for such variability (e.g.
, pharmacogenetics) and, more difficult, the variability in drug sensitivity. Our current means of drug dosing in children are largely empirical, based on body weight or surface area. Such empiricism assumes a linear relationship between size, enzyme, and drug transporter activity, and receptor expression. We must and should be able to do better. There is much work to be done, but it must be performed in children because the ability to extrapolate from animal models is limited.